Andreas P. Termin

Recent Advances in Voltage-Gated Sodium Channel Blockers: Therapeutic Potential as Drug Targets in the CNS

Publisher Summary This chapter summarizes developments within the voltage-gated sodium channel (VGSC) field focusing on the structural classes. The nine VGSCs (NaV1.1–1.9) discovered to date are members of a larger voltage-gated ion channel super-family which regulates the electrical activity among cells and tissues, and is involved in many physiological processes such as cognition, locomotion, and nociception. Of the nine VGSCs, NaV1.1, NaV1.2, NaV1.3, and NaV1.6 are distributed throughout the central nervous system (CNS). NaV1.4 is present in muscle tissue, and NaV1.5 is in cardiac myocytes, while NaV1.7, NaV1.8, and NaV1.9 are distributed in the peripheral nervous system (PNS). It is now known, however, that the expression of VGSCs can change significantly under pathological conditions such as neuropathic pain or multiple sclerosis (MS). For example, NaV1.8 mRNA and protein are up-regulated within cerebellar purkinje cells in animal models of MS and in human MS conditions. Similarly, mRNA for NaV1.8 is down-regulated in the dorsal root ganglia (DRG) but up-regulated in undamaged neurons in both rodent models of neuropathic pain and in human chronic pain conditions. The attention derived from the recent genetic studies of loss-of-function mutations of SCN9A (NaV1.7) in man has propelled these targets to the forefront of drug discovery.

Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists.

Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties.

Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors.

Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.